6-99435828-T-C

Variant names:

• chr6-99435828-T-C
• rs6570065
• NM_001346022.3:c.2333A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001346022.3(USP45):​c.2333A>G​(p.Asn778Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,612,634 control chromosomes in the GnomAD database, including 801,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.98 (73770 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727792 hom.)
• Consequence: USP45 NM_001346022.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.74
• Publications: 28 publications found

Genes affected

USP45 (HGNC:20080): (ubiquitin specific peptidase 45) The protein encoded by this gene is a deubiquitylase that binds ERCC1, the catalytic subunit of the XPF-ERCC1 DNA repair endonuclease. This endonuclease is a critical regulator of DNA repair processes, and the deubiquitylase activity of the encoded protein is important for maintaining the DNA repair ability of XPF-ERCC1. [provided by RefSeq, Sep 2016]

PNISR-AS1 (HGNC:40958): (PNISR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8804E-7).
• BP6: Variant 6-99435828-T-C is Benign according to our data. Variant chr6-99435828-T-C is described in ClinVar as Benign. ClinVar VariationId is 1684198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346022.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP45	NM_001346022.3	MANE Select	c.2333A>G	p.Asn778Ser	missense	Exon 18 of 18	NP_001332951.1	Q70EL2-1
	USP45	NM_001080481.3		c.2333A>G	p.Asn778Ser	missense	Exon 18 of 18	NP_001073950.1	Q70EL2-1
	USP45	NM_001346021.3		c.2333A>G	p.Asn778Ser	missense	Exon 18 of 18	NP_001332950.1	Q70EL2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP45	ENST00000500704.7	TSL:5 MANE Select	c.2333A>G	p.Asn778Ser	missense	Exon 18 of 18	ENSP00000424372.1	Q70EL2-1
	USP45	ENST00000327681.10	TSL:1	c.2333A>G	p.Asn778Ser	missense	Exon 18 of 18	ENSP00000333376.6	Q70EL2-1
	USP45	ENST00000496518.6	TSL:1	n.*1299A>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000421248.1	H0Y8J5

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149742 AN: 152188 Hom.: 73715 Cov.: 31

Gnomad AFR AF: 0.944

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.987

GnomAD2 exomes AF: 0.996 AC: 248587 AN: 249602 AF XY: 0.997

Gnomad AFR exome AF: 0.942

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.998 AC: 1457881 AN: 1460328 Hom.: 727792 Cov.: 43 AF XY: 0.999 AC XY: 725427 AN XY: 726428

African (AFR) AF: 0.939 AC: 31372 AN: 33422

American (AMR) AF: 0.998 AC: 44346 AN: 44446

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26102 AN: 26102

East Asian (EAS) AF: 1.00 AC: 39634 AN: 39634

South Asian (SAS) AF: 1.00 AC: 85858 AN: 85868

European-Finnish (FIN) AF: 1.00 AC: 53402 AN: 53402

Middle Eastern (MID) AF: 0.997 AC: 5743 AN: 5762

European-Non Finnish (NFE) AF: 1.00 AC: 1111314 AN: 1111368

Other (OTH) AF: 0.996 AC: 60110 AN: 60324

GnomAD4 genome AF: 0.984 AC: 149857 AN: 152306 Hom.: 73770 Cov.: 31 AF XY: 0.984 AC XY: 73314 AN XY: 74470

African (AFR) AF: 0.944 AC: 39238 AN: 41550

American (AMR) AF: 0.994 AC: 15192 AN: 15290

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5186

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68030 AN: 68040

Other (OTH) AF: 0.987 AC: 2087 AN: 2114

Alfa AF: 0.993 Hom.: 190692

Bravo AF: 0.981

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.938 AC: 4132

ESP6500EA AF: 1.00 AC: 8599

ExAC AF: 0.995 AC: 120784

Asia WGS AF: 0.997 AC: 3467 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Leber congenital amaurosis 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.3
DANN	Benign	0.83
DEOGEN2	Benign	0.00077	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.055	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.070
ClinPred		0.00092	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.072
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6570065; hg19: chr6-99883704; COSMIC: COSV107389229; COSMIC: COSV107389229;